This invention relates to radiation sources which may be transported on catheters and used to deliver radiation to prevent or slow restenosis of an artery traumatized such as by percutaneous transluminal angioplasty (PTA).
PTA treatment of the coronary arteries, percutaneous transluminal coronary angioplasty (PTCA), also known as balloon angioplasty, is the predominant treatment for coronary vessel stenosis. Approximately 300,000 procedures were performed in the United States in 1990 and nearly one million procedures worldwide in 1997. The U.S. market constitutes roughly half of the total market for this procedure. The increasing popularity of the PTCA procedure is attributable to its relatively high success rate, and its minimal invasiveness compared with coronary by-pass surgery. Patients treated by PTCA, however, suffer from a high incidence of restenosis, with about 35% or more of all patients requiring repeat PTCA procedures or by-pass surgery, with attendant high cost and added patient risk.
More recent attempts to prevent restenosis by use of drugs, mechanical devices, and other experimental procedures have had limited long term success. Stents, for example, dramatically reduce acute reclosure, and slow the clinical effects of smooth muscle cell proliferation by enlarging the minimum luminal diameter, but otherwise do nothing to prevent the proliferative response to the angioplasty induced injury.
Restenosis is now believed to occur at least in part as a result of injury to the arterial wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by hyperplastic growth of the vascular smooth muscle cells in the region traumatized by the angioplasty. Intimal hyperplasia or smooth muscle cell proliferation narrows the lumen that was opened by the angioplasty, regardless of the presence of a stent, thereby necessitating a repeat PTCA or other procedure to alleviate the restenosis.
Preliminary studies indicate that intravascular radiotherapy (IVRT) has promise in the prevention or long-term control of restenosis following angioplasty. IVRT may also be used to prevent or delay stenosis following cardiovascular graft procedures or other trauma to the vessel wall. Proper control of the radiation dosage, however, appears to be important to inhibit or arrest hyperplasia without causing excessive damage to healthy tissue. Overdosing of a section of blood vessel can cause arterial necrosis, inflammation, hemorrhaging, and other risks discussed below. Underdosing will result in inadequate inhibition of smooth muscle cell hyperplasia, or even exacerbation of hyperplasia and resulting restenosis.
The prior art contains many examples of catheter based radiation delivery systems. The simplest systems disclose seed train type sources inside closed end tubes. An example of this type of system can be found in U.S. Pat. No. 5,199,939 to Dake. In order to separate the radiation source from the catheter and allow re-use of the source, a delivery system is disclosed by U.S. Pat. No. 5,683,345 to Waksman et al. where radioactive source seeds are hydraulically driven into the lumen of a closed end catheter where they remain for the duration of the treatment, after which they are pumped back into the container. Later disclosures integrated the source wire into catheters more like the type common in interventional cardiology. In this type of device, a closed end lumen, through which is deployed a radioactive source wire, is added to a conventional catheter construction. A balloon is incorporated to help center the source wire in the lumen. It is supposed that the radioactive source wire would be delivered through the catheter with a commercial type afterloader system produced by a manufacturer such as Nucletron, BV. These types of systems are disclosed in Liprie U.S. Pat. No. 5,618,266, Weinberger U.S. Pat. No. 5,503,613, and Bradshaw U.S. Pat. No. 5,662,580.
In the systems disclosed by Dake and Waksman, the source resides in or very near the center of the catheter during treatment. However, it does not necessarily reside in the center of the artery. The systems disclosed by Weinberger and Bradshaw further include a centering mechanism, such as an inflatable balloon, to overcome this shortcoming. In either case, the source energies must be high enough to traverse the lumen of the blood vessel to get to the target tissue site in the vessel wall, thus requiring the use of higher energy sources. Higher energy sources, however, can have undesirable features. First, the likelihood of radiation inadvertently affecting untargeted tissue is higher because the absorption factor per unit tissue length is actually lower for higher energy radiation. Second, the higher energy sources are more hazardous to the medical staff and thus require additional shielding during storage and additional precaution during use. Third, the source may or may not be exactly in the center of the lumen, so the dose calculations are subject to larger error factors due to non-uniformity in the radial distance from the source surface to the target tissue. The impact of these factors is a common topic of discussion at recent medical conferences addressing Intravascular Radiation Therapy, such as the Trans Catheter Therapeutics conference, the Scripps Symposium on Radiotherapy, the Advances in Cardiovascular Radiation Therapy meeting, the American College of Cardiology meeting, and the American Heart Association Meeting.
The impact on treatment strategy is discussed in detail in a paper discussing a removable seed system similar to the ones disclosed above (Tierstein et al., Catheter based Radiotherapy to Inhibit Restenosis after Coronary Stenting, NEJM 1997; 336(24):1697-1703). Tierstein reports that Scripps Clinic physicians inspect each vessel using ultrasonography to assess the maximum and minimum distances from the source center to the target tissue. To prevent a dose hazard, they will not treat vessels where more than about a 4xc3x97 differential dose factor (8-30 Gy) exists between the near vessel target and the far vessel target. Differential dose factors such as these are inevitable for a catheter in a curvilinear vessel such as an artery, and will invariably limit the use of radiation and add complexity to the procedure. Moreover, the paper describes the need to keep the source in a lead transport device called a xe2x80x9cpigxe2x80x9d, as well as the fact that the medical staff leaves the catheterization laboratory during the treatment. Thus added complexity, time and risk is added to the procedure caused by variability of the position of the source within the delivery system and by the energy of the source itself.
In response to these dosimetry problems, several more inventions have been disclosed in an attempt to overcome the limitations of the high energy seed based systems. These systems share a common feature in that they attempt to bring the source closer to the target tissue. For example, U.S. Pat. No. 5,302,168 to Hess teaches the use of a radioactive source contained in a flexible carrier with remotely manipulated windows; Fearnot discloses a wire basket construction in U.S. Pat. No. 5,484,384 that can be introduced in a low profile state and then deployed once in place; Hess also purports to disclose a balloon with radioactive sources attached on the surface in U.S. Pat. No. 5,302,168; Hehrlein discloses a balloon catheter coated with an active isotope in WO 9622121; and Bradshaw discloses a balloon catheter adapted for use with a liquid isotope in U.S. Pat. No. 5,662,580. The purpose of all of these inventions is to place the source closer to the target tissue, thus improving the treatment characteristics.
In a non-catheter based approach, U.S. Pat. No. 5,059,166 to Fischell discloses an IVRT method that relies on a radioactive stent that is permanently implanted in the blood vessel after completion of the lumen opening procedure. Close control of the radiation dose delivered to the patient by means of a permanently implanted stent is difficult to maintain because the dose is entirely determined by the activity of the stent at the particular time it is implanted. In addition, current stents are generally not removable without invasive procedures. The dose delivered to the blood vessel is also non-uniform because the tissue that is in contact with the individual strands of the stent receive a higher dosage than the tissue between the individual strands. This non-uniform dose distribution may be especially disadvantageous if the stent incorporates a low penetration source such as a beta emitter.
Additional problems arise when conventional methods, such as ion implantation, are used to make a radioactive source for IVRT. Hehrlein describes the use of direct ion implantation of active P-32 in his paper xe2x80x9cPure xcex2-Particle-Emitting Stents Inhibit Neointima Formation in Rabbitsxe2x80x9d cited previously. While successfully providing a single mode of radiation using this method, the ion implantation process presents other limitations. For example, ion implantation is only about 10 to 30% efficient. In other words, only about one to three of every ten ions put into the accelerator is implanted on the target, and the remainder remains in the machine. Thus, the radiation level of the machine increases steadily with consistent use. With consistent use, the machine can become so radioactive that it must be shut down while the isotope decays away. Therefore, the isotope used must be of a relatively short half-life and/or the amount of radiation utilized in the process must be very small, in order to shorten the xe2x80x9ccooling offxe2x80x9d period. Moreover, the major portion of the isotope is lost to the process, implying increased cost to the final product.
Despite the foregoing, among many other advances in IVRT, there remains a need for an IVRT method and apparatus that delivers an easily controllable uniform dosage of radiation without the need for special devices or methods to center a radiation source in the lumen. Furthermore, a need remains for a method to make a source for IVRT which can be made without the complications and radioactive waste as seen with ion implantation methods.
There is provided in accordance with one aspect of the present invention, a radiation delivery source. The source comprises a substrate layer having at least a first side and an isotope layer on at least the first side of the substrate, wherein the isotope layer comprises a salt or oxide and at least one isotope. In one embodiment, the radiation delivery source further comprises an outer coating layer. The coating layer may comprise any of a variety of materials such as cyanoacrylates, acrylics, acrylates, ethylene methyl acrylate/acrylic acid, urethanes, polyvinylidene chloride, polybutylvinyl chloride, other polymers or combinations thereof. The outer coating layer may also comprise biocompatible materials such as heparin.
Preferably, the isotope in the isotope layer is selected from the group of gamma emitters with energies less than about 300 keV including I-125, Pd-103, As-73, and Gd-153, or the high energy beta group (Emax greater than 1.5 meV) including P-32, Y-90 and W/Re-188. Other isotopes not currently mentioned, can be utilized by the invention described herein. The selection of these isotopes, however, allows the source to be shielded in a material such as leaded acrylic in commercially available thickness of 15-30 mm, or in a lead tube of approximately 0.3-0.5 mm wall thickness. Some of the other isotopes which may be deemed suitable for use in the present invention or for a particular intended use, include Au-198, Ir-192, Co-60, Co-58, Ru-106, Rh-106, Cu-64, Ga-67, Fe-59, and Sr-90. The selection of an isotope may be influenced by its chemical and radiation properties.
In another aspect of the present invention, a radiation delivery source is provided having a substrate layer, a tie layer bound thereto, and an isotope layer bound to the tie layer. The tie layer comprises one or more materials selected from the group consisting of metals, metal salts, metal oxides, salts, alloys, polyester, polyimide, and other polymeric materials. The isotope layer comprises a relatively insoluble metal salt or oxide, and at least one isotope. In one embodiment, the source further comprises an outer coating layer.
In one embodiment, the substrate layer is a thin film layer, which may be attached to or which comprises at least a portion of an inflatable balloon.
In accordance with another aspect of the present invention, there is provided a method for making a radiation delivery source. The method comprises the steps of providing a substrate and coating the substrate with an isotope layer comprising a relatively insoluble salt of at least one isotope. In one embodiment, the coating step comprises the steps of coating the substrate with at least one layer of metal, reacting the layer of metal to form a metal oxide or metal salt, and exposing (e.g., dipping) the layer of metal oxide or metal salt to a solution comprising a plurality of isotope ions to form the isotope layer. In another embodiment, the coating step comprises the steps of coating the substrate with a layer of metal salt or metal oxide, exposing the layer of metal salt or metal oxide to a fluid comprising a plurality of isotope ions to form the isotope layer. In one embodiment, the method further comprises the step of coating the isotope layer with a coating layer.
In accordance with a further aspect of the present invention, there is provided a radiation delivery balloon catheter. The balloon catheter comprises an elongate flexible tubular body, having a proximal end and a distal end. An inflatable balloon is provided on the tubular body near the distal end thereof. The balloon is in fluid communication with an inflation lumen extending axially through the tubular body.
A thin film radiation source is provided on the balloon, said thin film source comprising a substrate and an isotope layer. In one embodiment, a tie layer is provided between the substrate and the isotope layer. In another embodiment, a coating layer is provided over the isotope layer. The substrate may comprise a portion of the wall of the balloon, or a separate substrate layer attached to the surface of the balloon. This isotope layer may be bound directly to, or impregnated within, the wall of the balloon. In one embodiment, a tubular outer sleeve is provided for surrounding the thin film radiation source and securing the radiation source to the balloon.
In another embodiment, the radiation delivery balloon catheter is provided with a proximal guidewire access port on the tubular body, positioned substantially distally of the proximal end of the tubular body, for providing rapid exchange capabilities. In addition to, or instead of the rapid exchange feature, the catheter may be provided with at least one proximal perfusion port on a proximal side of the balloon in fluid communication with at least one distal perfusion port on a distal side of the balloon, for permitting perfusion of blood across the balloon while the balloon is inflated at a treatment site.
In accordance with a further aspect of the present invention, there is provided a method of treating a site within a vessel. The method comprises the steps of identifying a site in a vessel to be treated, and providing a radiation delivery catheter having an expandable balloon with a thin film radiation delivery layer thereon. The radiation delivery layer preferably has a substrate layer and an isotope layer. The balloon is positioned within a treatment site, and inflated to position the radiation delivery layer adjacent the vessel wall. A circumferentially substantially uniform dose of radiation is delivered from the delivery balloon to the vessel wall. The balloon is thereafter deflated and removed from the treatment site.
In one embodiment, the method further comprises the steps of positioning a stent on the balloon prior to the positioning step, and expanding the stent at the treatment site to implant the stent.
In accordance with a further aspect of the present invention, the site identification step in the foregoing method comprises identifying a site having an implanted stent or graft. The balloon is positioned within the previously implanted stent or graft and expanded to deliver a radiation dose within the previously implanted stent or graft. The balloon may either be inflated to a relatively low inflation pressure, to bring the radiation source into contact with the interior wall of the stent or graft without further stent or graft expansion, or inflated to a relatively higher inflation pressure, to further expand the stent or graft while delivering a radiation dose.
In accordance with a further aspect of the present invention, there is provided a method of simultaneously performing balloon dilatation of a stenosis in a body lumen, and delivering radiation to the body lumen. The method comprises the steps of identifying a stenosis in a body lumen, and providing a treatment catheter having an elongate flexible tubular body with an inflation balloon near a distal end thereof, and a cylindrical thin film radiation delivery layer on the balloon. The balloon is percutaneously inserted and transluminally advanced through the body lumen, and positioned within the stenosis. The balloon is thereafter inflated to radially expand the vessel in the area of the stenosis, and simultaneously deliver radiation from the thin film to the vessel wall.
In accordance with another aspect of the present invention, there is provided a method of simultaneously performing a balloon dilatation of a stenosis in a body lumen, delivering a stent, and delivering radiation to the body lumen. The method comprises the steps of identifying a stenosis in a body lumen, and providing a treatment catheter having an elongate flexible tubular body with an inflation balloon near a distal end thereof, and a cylindrical thin film radiation delivery layer on the balloon. The balloon is percutaneously inserted and transluminally advanced through the body lumen, and positioned within the stenosis. The balloon is thereafter inflated to radially expand the vessel in the area of the stenosis, expand and deliver the stent and simultaneously deliver radiation from the thin film to the vessel wall.
In accordance with a further aspect of the present invention, there is provided a method of producing a radiation delivery catheter having a target activity. The method comprises the steps of providing a catheter dimensioned for insertion within a body lumen, and providing a thin film radiation source having a known radioactive activity per unit length. A sufficient length of the radiation source is wrapped around the catheter to produce a net radioactive activity of at least about the target activity. Preferably, the catheter is provided with a balloon, and the thin film radiation source is wrapped around the balloon. In one embodiment, the method further comprises the step of providing a protective tubular sheath around the radiation source, to secure the source to the catheter.
Further features and advantages of the present invention will become apparent to those of skill in the art in view of the detailed description of preferred embodiments which follow, when considered together with the attached drawings and claims.